This invention relates to peptide-containing xcex1-ketoamide inhibitors of cysteine and serine proteases, methods for making these compounds, and methods for using the same.
Numerous cysteine and serine proteases have been identified in human tissues. A xe2x80x9cproteasexe2x80x9d is an enzyme which degrades proteins into smaller components (peptides). The terms xe2x80x9ccysteine proteasexe2x80x9d and xe2x80x9cserine proteasexe2x80x9d refer to proteases which are distinguished by the presence therein of a cysteine or serine residue which plays a critical role in the catalytic process. Mammalian systems, including humans, normally degrade and process proteins via a variety of enzymes including cysteine and serine proteases. However, when present at elevated levels or when abnormally activated, cysteine and serine proteases may be involved in pathophysiological processes.
For example, calcium-activated neutral proteases (xe2x80x9ccalpainsxe2x80x9d) comprise a family of intracellular cysteine proteases which are ubiquitously expressed in mammalian tissues. Two major calpains have been identified; calpain I and calpain II. While calpain II is the predominant form in many tissues, calpain I is thought to be the predominant form in pathological conditions of nerve tissues. The calpain family of cysteine proteases has been implicated in many diseases and disorders, including neurodegeneration, stroke, Alzheimer""s, amyotrophy, motor neuron damage, acute central nervous system injury, muscular dystrophy, bone resorption, platelet aggregation, cataracts and inflammation. Calpain I has been implicated in excitatory amino-acid induced neurotoxicity disorders including ischemia, hypoglycemia, Huntington""s Disease, and epilepsy. The lysosomal cysteine protease cathepsin B has been implicated in the following disorders: arthritis, inflammation, myocardial infarction, tumor metastasis, and muscular dystrophy. Other lysosomal cysteine proteases include cathepsins C, H, L and S. Interleukin-1xcex2 converting enzyme (xe2x80x9cICExe2x80x9d) is a cysteine protease which catalyzes the formation of interleukin-1xcex2. Interleukin-1xcex2 is an immunoregulatory protein implicated in the following disorders: inflammation, diabetes, septic shock, rheumatoid arthritis, and Alzheimer""s disease. ICE has also been linked to apoptotic cell death of neurons, which is implicated in a variety of neurodegenerative disorders including Parkinson""s disease, ischemia, and amyotrophic lateral sclerosis (ALS).
Cysteine proteases are also produced by various pathogens. The cysteine protease clostripain is produced by Clostridium histolyticum. Other proteases are produced by Trypanosoma cruzi, malaria parasites Plasmodium falciparum and P.vinckei and Streptococcus. Hepatitis A viral protease HAV C3 is a cysteine protease essential for processing of picornavirus structural proteins and enzymes.
Exemplary serine proteases implicated in degenerative disorders include thrombin, human leukocyte elastase, pancreatic elastase, chymase and cathepsin G. Specifically, thrombin is produced in the blood coagulation cascade, cleaves fibrinogen to form fibrin and activates Factor VIII; thrombin is implicated in thrombophlebitis, thrombosis and asthma. Human leukocyte elastase is implicated in tissue degenerative disorders such as rheumatoid arthritis, osteoarthritis, atherosclerosis, bronchitis, cystic fibrosis, and emphysema. Pancreatic elastase is implicated in pancreatitis. Chymase, an enzyme important in angiotensin synthesis, is implicated in hypertension, myocardial infarction, and coronary heart disease. Cathepsin G is implicated in abnormal connective tissue degradation, particularly in the lung.
Given the link between cysteine and serine proteases and various debilitating disorders, compounds which inhibit these proteases would be useful and would provide an advance in both research and clinical medicine. The present invention is directed to these, as well as other, important ends.
The present invention is directed to selected peptide-containing xcex1-ketoamide inhibitors of cysteine and serine proteases represented by the general formula I: 
wherein:
Q has the formula Gxe2x80x94Bxe2x80x94(CHR4)v where R4 is independently H or alkyl having from 1 to 4 carbons;
v is 0, 1, or 2;
B is selected from the group consisting of C(xe2x95x90O), OC(xe2x95x90O), S(xe2x95x90O)m, CH2, a bond, NR5C(xe2x95x90O), S(xe2x95x90O)mxe2x80x94Axe2x80x94C(xe2x95x90O), and C(xe2x95x90O)xe2x80x94Axe2x80x94C(xe2x95x90O), where R5 is H or lower alkyl;
m is 0, 1, or 2;
A is lower alkylene or cycloalkylene, optionally substituted with one or more halogen atoms, aryl, or heteroaryl groups;
M is a carbon atom;
G is selected from the group consisting of H, a blocking group, lower alkyl, lower alkenyl, aryl having from about 6 to about 14 carbons, heterocyclyl having from about 5 to about 14 ring atoms, heterocycloalkyl having from about 5 to about 14 ring atoms, arylalkyl having from about 7 to about 15 carbons, heteroarylalkyl, and arylheteroalkyl wherein the aryl portion can be unfused or fused with the heteroalkyl ring, said alkyl, aryl, heterocyclyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, and arylheteroalkyl groups being optionally substituted with one or more J groups;
J is selected from the group consisting of halogen, CN, nitro, lower alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, halogenated alkyl, aryloxyalkyl, alkylthio, alkylsulfonyl, aryl, heteroaryl, arylalkyl, arylalkyloxy, arylsulfonyl, heteroarylsulfonyl, alkoxycarbonyl, alkoxyalkyl, acyl, alkoxy, hydroxy, carboxy, hydroxyalkyl, amino, alkylamino, and aminoalkyl, said amino group or said amino group of said aminoalkyl or alkylamino group being optionally substituted with an acyl group, an alkoxy group, or with 1 to 3 aryl, lower alkyl, cycloalkyl, or alkoxyalkyl groups; and said aryl, heteroaryl, heterocycloalkyl, and heteroalkyl groups being further optionally substituted by a J group;
each Aaa is independently an amino acid which optionally contains one or more blocking groups;
n is 0, 1, 2, or 3;
R1 and R2 are independently selected from the group consisting of H, alkyl having from one to about 6 carbons, arylalkyl having from about 7 to about 15 carbons, heteroalkyl in which the ring contains from about 5 to about 14 ring atoms, heteroarylalkyl in which the heteroaryl ring contains from about 5 to about 14 ring atoms, alkoxyalkyl, a side chain of a naturally occurring amino acid in the R or S configuration, and (CH2)pNHxe2x80x94L, said alkyl, arylalkyl, heteroalkyl, heteroarylalkyl, and alkoxyalkyl groups being optionally substituted with one or more J groups;
p is 0, 1, 2, or 3;
L is selected from the group consisting of alkoxycarbonyl having from 2 to about 7 carbons, arylalkoxycarbonyl in which the arylalkoxy group contains about 7 to about 15 carbons, and S(xe2x95x90O)2R6;
R6 is selected from the group consisting of lower alkyl, and aryl having from about 6 to about 14 carbons;
R3 is selected from the group consisting of H, alkyl having from one to about 6 carbons, arylalkyl having from about 7 to about 15 carbons, heteroalkyl in which the ring contains from about 5 to about 14 ring atoms, heteroarylalkyl in which the heteroaryl ring contains from about 5 to about 14 ring atoms, alkoxyalkyl, a side chain of a naturally occurring amino acid in the R or S configuration, (CH2)pNHxe2x80x94L, C(xe2x95x90O)R7, S(xe2x95x90O)2R7, a blocking group, and when combined with the carbon atom to which R1 is attached an alkylene group having from 2 to 5 carbons, said alkylene group being optionally substituted with a group selected from the group consisting of aryl, azide, CN, a protected amino group, and OSO2-aryl, said alkyl, arylalkyl, heteroalkyl, heteroarylalkyl, and alkoxyalkyl groups being optionally substituted with one or more J groups;
R7 is selected from the group consisting of aryl having from about 6 to about 14 carbons, heteroaryl having from about 5 to about 14 ring atoms, arylalkyl having from about 7 to about 15 carbons, alkyl having from 1 to about 10 carbons, said aryl, heteroaryl, arylalkyl and alkyl groups being optionally substituted with one or more J groups, heteroalkyl having from 2 to about 7 carbons, alkoxy having from about 1 to about 10 carbons, and amino optionally substituted with 1 or more alkyl groups;
q is 0 or 1;
Z is selected from the group consisting of C(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94Xxe2x80x94A1xe2x80x94K and 
X is a bond or xe2x80x94Oxe2x80x94;
A1 is the same as A;
K is selected from the group consisting of N(R10)Y, 
and SO2N(R8) (R10);
D is a fused aryl or heteroaryl group;
R11 is selected from the group consisting of alkoxy, aryloxy, and NHR12;
R12 is selected from the group consisting of H, alkyl, aryl, and heteroaryl, said alkyl, aryl or heteroaryl groups being optionally substituted with one or more J groups;
Y is selected from the group consisting of SO2R8, C(xe2x95x90O)NHR9, C(xe2x95x90S)NHR9, C(xe2x95x90NCN)R11, C(xe2x95x90NC(xe2x95x90O)NHR10)R11, and CO2R8;
R8 is selected from the group consisting of alkyl, alkoxy, aryl, and heterocyclyl, said alkyl, alkoxy, aryl, or heterocyclyl groups being optionally substituted with one or more J groups;
R9 is selected from the group consisting of H, alkyl, aryl, and heteroaryl, said alkyl, aryl, or heteroaryl groups being optionally substituted with one or more J groups;
or an R9 alkyl group may be combined with an A1 alkylene group to form a N-containing heterocyclic 5- or 6-membered ring;
R10 is selected from the group consisting of H and lower alkyl;
or in the moiety SO2N(R8)R10, R8 and R10 may be combined together with the N atom to which they are attached to form a N-containing heterocyclic 5- or 6-membered ring;
or where A1 is an alkylene group, and K is N(R10)Y wherein R10 is alkyl, said R10 alkyl group may be combined with said A1 alkylene group to form a N-containing heterocyclic 5- or 6-membered ring; or a pharmaceutically acceptable salt thereof.
In some preferred embodiments of the compounds of Formula I, n and v are each 0, q is 1, B is a bond, and G is H. In further preferred embodiments of the compounds of Formula I, R1 is the sidechain of a naturally occurring amino acid. In still further preferred embodiments of the compounds of Formula I, R3 is xe2x80x94S(xe2x95x90C)2R7.
In some preferred embodiments of the compounds of Formula I, R2 is benzyl or alkoxyalkyl. In more preferred embodiments, X is a bond, and Y is SO2R8. Preferably, A1 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94, or xe2x80x94(CH3)CHxe2x80x94CH2xe2x80x94.
In further preferred embodiments of the compounds of Formula I, R1 is a serine sidechain, which is optionally capped with a benzyl group. Preferably, the carbon to which the serine sidechain is attached, designated xe2x80x9cMxe2x80x9d in Formula I, is a carbon atom in the D configuration.
In preferred embodiments of the compounds of Formula I, R2 is benzyl, R7 is methyl, and R8 is substituted phenyl, unsubstituted phenyl, substituted heteroaryl, or unsubstituted heteroaryl. In particularly preferred embodiments, R8 is aryl, aryl substituted with amino, aryl substituted with heterocyclomethyl, heteroaryl, alkyl substituted with heteroaryl, or heteroaryl substituted with alkylthio, haloalkyl, alkyl, phenylsulfonyl, halogen, aminophenyl, amino, or dialkylaminoalkyl.
In further preferred embodiments of the compounds of Formula I, n, v and q are each 0, B is (Cxe2x95x90O), and G is phenyl or lower alkyl, said phenyl or lower alkyl groups being optionally substituted with one or more J groups.
In more preferred embodiments of the invention, n and v are each 0, q is 1, R1 is the side chain of an amino acid in the D- or L-configuration, R3 is S(xe2x95x90O)2R7, G is H, B is a bond, R2 is benzyl or alkoxyalkyl, X is a bond, and Y is SO2R8.
In other preferred embodiments, A1 is CH2CH2, CH2CH(CH3), or (CH3)CHCH2. In more preferred embodiments, R1 is a serine side chain in the D-configuration in which the hydroxyl group is capped with benzyl, R2 is benzyl, R7 is methyl, and R8 is substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl.
More preferred are the substituents shown for R1-R4, B, G, Aaa, X, A1, Y, n, q and v shown for the compounds in Tables 2, 3, 4 and 5. Especially preferred are the substituents shown for compounds 9, 13, 17, 22, and 29-151.
Some especially preferred embodiments of the compounds of Formula I are shown in Tables 2, 3, 4 and 5, infra, with compounds 9, 13, 17, 22, and 29-151 being particularly preferred.
Because the peptide-containing xcex1-ketoamides of the invention inhibit cysteine proteases and serine proteases, they can be used in both research and therapeutic settings.
In a research environment, preferred compounds having defined attributes can be used to screen for natural and synthetic compounds which evidence similar characteristics in inhibiting protease activity. The compounds can also be used in the refinement of in vitro and in vivo models for determining the effects of inhibition of particular proteases on particular cell types or biological conditions.
In a therapeutic setting, given the connection between cysteine proteases and certain defined disorders, and serine proteases and certain defined disorders, compounds of the invention can be utilized to alleviate, mediate, reduce and/or prevent disorders which are associated with abnormal and/or aberrant activity of cysteine proteases and/or serine proteases.
In preferred embodiments, compositions are provided for inhibiting a serine protease or a cysteine protease comprising a compound of the invention and a pharmaceutically acceptable carrier. In other preferred embodiments, methods are provided for inhibiting serine proteases or cysteine proteases comprising contacting a protease selected from the group consisting of serine proteases and cysteine proteases with an inhibitory amount of a compound of the invention.
Methodologies for making the present peptide-containing xcex1-ketoamide inhibitors are also disclosed. Other useful methodologies will be apparent to those skilled in the art, once armed with the present disclosure. These and other features of the compounds of the subject invention are set forth in more detail below.
Disclosed herein are the selected peptide-containing xcex1-ketoamides which are represented by the following formula I: 
wherein:
Q has the formula Gxe2x80x94Bxe2x80x94(CHR4)v where R4 is independently H or alkyl having from 1 to 4 carbons;
v is 0, 1, or 2;
B is selected from the group consisting of C(xe2x95x90O), OC(xe2x95x90O), S(xe2x95x90O)m, CH2, a bond, NR5C(xe2x95x90O), S(xe2x95x90O)mxe2x80x94Axe2x80x94C(xe2x95x90O), and C(xe2x95x90O)xe2x80x94Axe2x80x94C(xe2x95x90O), where R5 is H or lower alkyl;
m is 0, 1, or 2;
A is lower alkylene or cycloalkylene, optionally substituted with one or more halogen atoms, aryl, or heteroaryl groups;
M is a carbon atom;
G is selected from the group consisting of H, a blocking group, lower alkyl, lower alkenyl, aryl having from about 6 to about 14 carbons, heterocyclyl having from about 5 to about 14 ring atoms, heterocycloalkyl having from about 5 to about 14 ring atoms, arylalkyl having from about 7 to about 15 carbons, heteroarylalkyl, and arylheteroalkyl wherein the aryl portion can be unfused or fused with the heteroalkyl ring, said alkyl, aryl, heterocyclyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, and arylheteroalkyl groups being optionally substituted with one or more J groups;
J is selected from the group consisting of halogen, CN, nitro, lower alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, halogenated alkyl, aryloxyalkyl, alkylthio, alkylsulfonyl, aryl, heteroaryl, arylalkyl, arylalkyloxy, arylsulfonyl, heteroarylsulfonyl, alkoxycarbonyl, alkoxyalkyl, acyl, alkoxy, hydroxy, carboxy, hydroxyalkyl, amino, alkylamino, and aminoalkyl, said amino group or said amino group of said aminoalkyl or alkylamino group being optionally substituted with an acyl group, an alkoxy group, or with 1 to 3 aryl, lower alkyl, cycloalkyl, or alkoxyalkyl groups; and said aryl, heteroaryl, heterocycloalkyl, and heteroalkyl groups being further optionally substituted by a J group;
each Aaa is independently an amino acid which optionally contains one or more blocking groups;
n is 0, 1, 2, or 3;
R1 and R2 are independently selected from the group consisting of H, alkyl having from one to about 6 carbons, arylalkyl having from about 7 to about 15 carbons, heteroalkyl in which the ring contains from about 5 to about 14 ring atoms, heteroarylalkyl in which the heteroaryl ring contains from about 5 to about 14 ring atoms, alkoxyalkyl, a side chain of a naturally occurring amino acid in the R or S configuration, and (CH2)pNHxe2x80x94L, said alkyl, arylalkyl, heteroalkyl, heteroarylalkyl, and alkoxyalkyl groups being optionally substituted with one or more J groups;
p is 0, 1, 2, or 3;
L is selected from the group consisting of alkoxycarbonyl having from 2 to about 7 carbons, arylalkoxycarbonyl in which the arylalkoxy group contains about 7 to about 15 carbons, and S(xe2x95x90O)2R6;
R6 is selected from the group consisting of lower alkyl, and aryl having from about 6 to about 14 carbons;
R3 is selected from the group consisting of H, alkyl having from one to about 6 carbons, arylalkyl having from about 7 to about 15 carbons, heteroalkyl in which the ring contains from about 5 to about 14 ring atoms, heteroarylalkyl in which the heteroaryl ring contains from about 5 to about 14 ring atoms, alkoxyalkyl, a side chain of a naturally occurring amino acid in the R or S configuration, (CH2)pNHxe2x80x94L, C(xe2x95x90O)R7, S(xe2x95x90O)2R7, a blocking group, and when combined with the carbon atom to which R1 is attached an alkylene group having from 2 to 5 carbons, said alkylene group being optionally substituted with a group selected from the group consisting of aryl, azide, CN, a protected amino group, and OSO2-aryl, said alkyl, arylalkyl, heteroalkyl, heteroarylalkyl, and alkoxyalkyl groups being optionally substituted with one or more J groups;
R7 is selected from the group consisting of aryl having from about 6 to about 14 carbons, heteroaryl having from about 5 to about 14 ring atoms, arylalkyl having from about 7 to about 15 carbons, alkyl having from 1 to about 10 carbons, said aryl, heteroaryl, arylalkyl and alkyl groups being optionally substituted with one or more J groups, heteroalkyl having from 2 to about 7 carbons, alkoxy having from about 1 to about 10 carbons, and amino optionally substituted with 1 or more alkyl groups;
q is 0 or 1;
Z is selected from the group consisting of C(xe2x95x90O)C(xe2x95x90O)NHxe2x80x94Xxe2x80x94A1xe2x80x94K and 
X is a bond or xe2x80x94Oxe2x80x94;
A1 is the same as A;
K is selected from the group consisting of N(R10)Y, 
and SO2N(R8) (R10);
D is a fused aryl or heteroaryl group;
R11 is selected from the group consisting of alkoxy, aryloxy, and NHR12;
R12 is selected from the group consisting of H, alkyl, aryl, and heteroaryl, said alkyl, aryl or heteroaryl groups being optionally substituted with one or more J groups;
Y is selected from the group consisting of SO2R8, C(xe2x95x90O)NHR9, C(xe2x95x90S)NHR9, C(xe2x95x90NCN)R11, C(xe2x95x90NC(xe2x95x90O)NHR10)R11, and CO2R8;
R8 is selected from the group consisting of alkyl, alkoxy, aryl, and heterocyclyl, said alkyl, alkoxy, aryl, or heterocyclyl groups being optionally substituted with one or more J groups;
R9 is selected from the group consisting of H, alkyl, aryl, and heteroaryl, said alkyl, aryl, or heteroaryl groups being optionally substituted with one or more J groups;
or an R9 alkyl group may be combined with an A1 alkylene group to form a N-containing heterocyclic 5- or 6-membered ring;
R10 is selected from the group consisting of H and lower alkyl;
or in the moiety SO2N(R8)R10, R8 and R10 may be combined together with the N atom to which they are attached to form a N-containing heterocyclic 5- or 6-membered ring;
or where A1 is an alkylene group, and K is N(R10)Y wherein R10 is alkyl, said R10 alkyl group may be combined with said A1 alkylene group to form a N-containing heterocyclic 5- or 6-membered ring; or a pharmaceutically acceptable salt thereof.
It is recognized that various stereoisomeric forms of the compounds of Formula I may exist. Preferred compounds of the invention have any Aaa groups being xcex1-amino acids in the L-configuration. However, racemates and individual enantiomers and mixtures thereof form part of the present invention.
The carbon atom designated as xe2x80x9cMxe2x80x9d in the compounds of Formula I can exist in either the D or the L configuration. In some preferred embodiments, M is a carbon atom having the xe2x80x9cDxe2x80x9d configuration.
As used herein, the term xe2x80x9calkylxe2x80x9d includes straight-chain, and branched hydrocarbon groups such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-ethylpentyl, hexyl, and octyl groups. xe2x80x9cCycloalkylxe2x80x9d groups are cyclic alkyl groups, such as, for example, cyclopropyl, methylcyclopentyl, and cyclohexyl groups. Preferred alkyl groups have 1 to about 10 carbon atoms, most preferably xe2x80x9clower alkylxe2x80x9d of 1 to about 6 carbon atoms. xe2x80x9cAlkylenexe2x80x9d groups are alkyl groups having two points of attachment; i.e., non-terminal alkyl groups. xe2x80x9cLower alkylenexe2x80x9d groups are branched or unbranched alkylene groups of 1 to about 6 carbon atoms such as, for example, ethylene(xe2x80x94CH2CH2xe2x80x94), propylene, butylene, hexylene, 1-methylethylene, 2-methylethylene, and 2-methylpropylene. xe2x80x9cCycloalkylenexe2x80x9d groups are cyclic alkylene groups. xe2x80x9cAcylxe2x80x9d groups are alkylcarbonyl groups. xe2x80x9cArylxe2x80x9d groups are aromatic cyclic compounds preferably including but not limited to phenyl, tolyl, naphthyl, anthracyl, phenanthryl, and pyrenyl. Also included within the definition of xe2x80x9carylxe2x80x9d are ring systems having two aromatic rings connected by a bond, such as biphenyl. Preferred aryl groups include phenyl and naphthyl.
The term xe2x80x9ccarbocyclicxe2x80x9d, as used herein, refers to cyclic groups in which the ring portion is composed solely of carbon atoms. The term xe2x80x9chalogenxe2x80x9d refers to F, Cl, Br, and I atoms. The term xe2x80x9carylalkylxe2x80x9d denotes alkyl groups which bear aryl groups, for example, benzyl groups. As used herein, xe2x80x9calkoxyxe2x80x9d groups are alkyl groups linked through an oxygen atom. Examples of alkoxy groups include methoxy (xe2x80x94OCH3) and ethoxy (xe2x80x94OCH2CH3) groups. In general, the term xe2x80x9coxyxe2x80x9d when used as a suffix denotes attachment through an oxygen atom. Thus, alkoxycarbonyl groups are carbonyl groups which contain an alkoxy substituent, i.e., groups of general formula xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R, where R is alkyl. The term xe2x80x9calkoxyalkylxe2x80x9d denotes an alkoxy group attached to an alkyl group. The term xe2x80x9caryloxyxe2x80x9d denotes an aryl group linked through an oxygen atom, and the term xe2x80x9carylalkyloxyxe2x80x9d denotes an arylalkyl group linked through an oxygen atom.
The terms xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d, and xe2x80x9cheterocyclicxe2x80x9d refer to cyclic groups in which a ring portion includes at least one heteroatom such as O, N or S. Heterocyclic groups include xe2x80x9cheteroarylxe2x80x9d as well as xe2x80x9cheteroalkylxe2x80x9d groups. The term xe2x80x9cheteroarylxe2x80x9d denotes aryl groups having one or more hetero atoms (e.g., O, N, or S) contained within an aromatic ring. Also included within the definition of xe2x80x9cheteroarylxe2x80x9d are ring systems having two aromatic rings connected by a bond, where at least one of the rings contains a hetero atom. Preferred xe2x80x9cheteroarylxe2x80x9d groups include pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, imidazolyl, triazolyl, tetrazolyl, quinolyl, isoquinolyl, benzoimidazolyl, thiazolyl, bipyridyl, pyridylthiophenyl, pyrimidylthiophenyl, benzimidazolyl, isoxazolylthiophenyl, pyrazolylthiophenyl, phthalimido, and benzothiazolyl. The term xe2x80x9cheterocycloalkylxe2x80x9d denotes a heterocycle attached through a lower alkyl group. The term xe2x80x9cheteroarylalkylxe2x80x9d denotes a heteroaryl group attached through an alkyl group. As used herein, the term xe2x80x9cheteroalkylxe2x80x9d denotes a heterocyclic group which contains at least one saturated carbon atom in a heterocyclic ring. Examples of heteroalkyl groups include piperidine, dihydropyridine, and tetrahydroisoquinyl groups. The term xe2x80x9carylheteroalkylxe2x80x9d as used herein denotes axe2x80x9cheteroalkylxe2x80x9d group connected through an aryl group. One preferred example of an arylheteroalkyl group is dibenzo-xcex3-pyranyl.
As used herein, the term xe2x80x9camino acidxe2x80x9d denotes a molecule containing both an amino group and a carboxyl group. As used herein the term xe2x80x9cL-amino acidxe2x80x9d denotes an xcex1-amino acid having the L-configuration around the xcex1-carbon, that is, a carboxylic acid of general formula CH(COOH)(NH2)-(side chain), having the L-configuration. The term xe2x80x9cD-amino acidxe2x80x9d similarly denotes a carboxylic acid of general formula CH(COOH)(NH2)-(side chain), having the D-configuration around the xcex1-carbon. Side chains of L-amino acids include naturally occurring and non-naturally occurring moieties. Nonnaturally occurring (i.e., unnatural) amino acid side chains are moieties that are used in place of naturally occurring amino acid sidechains in, for example, amino acid analogs. See, for example, Lehninger, Biochemistry, Second Edition, Worth Publishers, Inc, 1975, pages 73-75. One representative amino acid side chain is the lysyl side chain, xe2x80x94(CH2)4xe2x80x94NH2. Other representative xcex1-amino acid side chains are shown below in Table 1.
Functional groups present in the compounds of Formula I may contain blocking groups. Blocking groups are known per se as chemical functional groups that can be selectively appended to functionalities, such as hydroxyl groups, amino groups, thio groups, and carboxyl groups. Protecting groups are blocking groups which can be readily removed from functionalities. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be employed with the present invention. Examples of such protecting groups are the benzyloxycarbonyl (Cbz; Z), toluenesulfonyl, t-butoxycarbonyl, methyl ester, and benzyl ether groups. Other preferred protecting groups according to the invention may be found in Greene, T. W. and Wuts, P. G. M., xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d 2d. Ed., Wiley and Sons, 1991, which is hereby incorporated by reference in its entirety.
Further blocking groups useful in the compounds of the present invention include those that bear acyl, aroyl, alkyl, alkanesulfonyl, arylalkanesulfonyl, or arylsulfonyl substituents on their amino groups. Other useful blocking groups include alkyl ethers, e.g., the methyl ether of serine.
The disclosed compounds of the invention are useful for the inhibition of cysteine proteases and serine proteases. As used herein, the terms xe2x80x9cinhibitxe2x80x9d and xe2x80x9cinhibitionxe2x80x9d mean having an adverse effect on enzymatic activity. An inhibitory amount is an amount of a compound of the invention effective to inhibit a cysteine and/or serine protease.
Pharmaceutically acceptable salts of the cysteine and serine protease inhibitors also fall within the scope of the compounds as disclosed herein. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d as used herein means an inorganic acid addition salt such as hydrochloride, sulfate, and phosphate, or an organic acid addition salt such as acetate, maleate, fumarate, tartrate, and citrate. Examples of pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt. Examples of pharmaceutically acceptable organic amine addition salts are salts with morpholine and piperidine. Examples of pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine, and phenylalanine.
Compounds provided herein can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable nontoxic excipients and carriers. As noted above, such compositions may be prepared for use in parenteral administration, particularly in the form of liquid solutions or suspensions; or oral administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermally, via, for example, transdermal patches; or prepared in other suitable fashions for these and other forms of administration as will be apparent to those skilled in the art.
The composition may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington""s Pharmaceutical Sciences (Mack Pub. Co., Easton, Pa., 1980). Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils and vegetable origin, hydrogenated naphthalenes and the like. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds. Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, cyclodextrins and liposomes. Formulations for inhalation administration contain as excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for parenteral administration may also include glycocholate for buccal administration, a salicylate for rectal administration, or citric acid for vaginal administration. Formulations for transdermal patches are preferably lipophilic emulsions.
The materials for this invention can be employed as the sole active agent in a pharmaceutical or can be used in combination with other active ingredients which could facilitate inhibition of cysteine and serine proteases in diseases or disorders.
The concentrations of the compounds described herein in a therapeutic composition will vary depending upon a number of factors, including the dosage of the drug to be administered, the chemical characteristics (e.g., hydrophobicity) of the compounds employed, and the route of administration. In general terms, the compounds of this invention may be provided in effective inhibitory amounts in an aqueous physiological buffer solution containing about 0.1 to 10% w/v compound for parenteral administration. Typical dose ranges are from about 1 xcexcg/kg to about 1 g/kg of body weight per day; a preferred dose range is from about 0.01 mg/kg to 100 mg/kg of body weight per day. Such formulations typically provide inhibitory amounts of the compound of the invention. The preferred dosage of drug to be administered is likely, however, to depend on such variables as the type or extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, and formulation of the compound excipient, and its route of administration.
As used herein, the term xe2x80x9ccontactingxe2x80x9d means directly or indirectly causing at least two moieties to come into physical association with each other. Contacting thus includes physical acts such as placing the moieties together in a container, or administering moieties to a patient. Thus, for example administering a compound of the invention to a human patient evidencing a disease or disorder associated with abnormal and/or aberrant activity of such proteases falls within the scope of the definition of the term xe2x80x9ccontactingxe2x80x9d.
The invention is further illustrated by way of the following examples which are intended to elucidate the invention. These examples are not intended, nor are they to be construed, as limiting the scope of the disclosure.